Project Abstract Alzheimer?s disease (AD) is the leading cause of dementia and is characterized by the accumulation of amyloid species into extracellular plaque as well as hyperphosphorylated intracellular tau tangles. Microglia, the immune cells of the brain, play a critical role in clearance of amyloid species via phagocytosis and contribute to neuroinflammation in AD via the production of inflammatory cytokines. Thus, understanding the molecular mechanisms that facilitate microglial phagocytosis and suppression of inflammation will be critical to developing highly targeted therapies. Our lab and others have observed a robust increase in expression of the Axl receptor on microglia directly surrounding amyloid plaque. Axl, a receptor tyrosine kinase, is a lucrative target to study in the context of AD due to its downstream signaling that includes both initiation of phagocytosis and activation of transcription factors suppressing the production of proinflammatory cytokines. However, there is a distinct paucity of literature examining the role of Axl in microglia and in the context of AD. I hypothesize that activation of Axl drives microglial phagocytosis of amyloid species and reduces the inflammatory environment around plaque in AD. Aim 1 will utilize in vitro techniques to explore phagocytosis of amyloid species using multiple microglial cell lines during stimulation with the Axl ligand, Gas6, and inhibition with the small molecule Axl inhibitor, R428. Aim 2 seeks to explore my hypothesis using overexpression of Gas6 via an adeno-associated viral vector in transgenic AD mice as well as chronic injections of the Axl inhibitor BMS-777607. Behavioral outcomes, amyloid plaque burden, extent of microglial phagocytosis of amyloid, and cytokine production will be quantified. Based on our data and the current literature, I hypothesize that activation of Axl using Gas6 will decrease plaque burden via increased microglial phagocytosis of plaque while simultaneously decreasing the inflammatory environment, and that administration of the Axl inhibitor will produce decreased microglial phagocytosis and increased production of proinflammatory cytokines. Together, the experimental results generated by these aims will contribute to understanding the role of microglia as mediators of amyloid clearance and regulation of inflammation in AD. The breadth of techniques required to complete these aims, as well as the clinical experience, professional development activities, and opportunity for inter- and intra-institutional collaboration as described in my training plan will provide me with excellent training to help me attain my goal of becoming a physician-scientist in the field of neurodegeneration.